Burns
Burns are among the oldest, most complex and painful injuries known. Dating to antiquity, humans have been battling the devastating effects of burns. Burns are the second leading cause of accidental death in the United States, with post burn care being traumatic, painful, lengthy and emotionally draining for the patient. In fact, it has been estimated that over five million people are involved in burn accidents in the United States each year. Approximately 150,000 of these patients are hospitalized and over 6000 of these die each year (1).
Thermal burns are by far the most common types of burns. Although the skin is usually the part of the body that is burned, the tissues under the skin can also be burned, and internal organs can be burned even when the skin is not. For example, drinking a very hot liquid or caustic substance such as acid can burn the esophagus and stomach. Inhaling smoke or hot air from a fire in a burning building can burn the lungs. Tissues that are burned may die. When tissues are damaged by a burn, fluid may leak from blood vessels (capilliary permeability), causing swelling or edema. In an extensive burn, loss of a large amount of fluid from abnormally leaky blood vessels can cause shock. In shock, blood pressure decreases so much that too little blood flows to the brain and other vital organs.
Electrical burns may be caused by a temperature of more than 9,000° F., generated by an electric current when it passes from the electrical source to the body; this type of burn, sometimes called an electrical arc burn, usually completely destroys and chars the skin at the current's point of entry into the body. Because the resistance (the body's ability to stop or slow the current's flow) is high where the skin touches the current's source, much of the electrical energy is converted into heat there, burning the surface. Most electrical burns also severely damage the tissues under the skin. These burns vary in size and depth and may affect an area much larger than that indicated by the area of injured skin. Large electrical shocks can paralyze breathing and disturb heart rhythm, causing dangerously irregular heartbeats.
Chemical burns can be caused by various irritants and poisons, including strong acids and alkalis, phenols and cresols (organic solvents), mustard gas, and phosphorus. Chemical burns can cause tissue death that can slowly spread for hours after the burn.
Radiation burns can be caused by nuclear weapons, nuclear accidents, laboratory exposure, accidents during X-ray radiation chemotherapy, and over-exposure to sun. Radiation burns can cause inflammation, edema, ulcerations, damage to underlying endothelium and other cell types, as well as mutagenesis resulting in cancer, especially hematologic malignancies.
After suffering a burn injury, the affected individual can have usually has severe protein, muscle, and fat wasting in the area of the burn (1). Indeed, loss of up to 20% of body protein may occur in the first two weeks following a third degree or deep tissue burn injury (2). Increased oxygen consumption, metabolic rate, urinary nitrogen excretion, fat breakdown and steady erosion of body mass are all directly related to burn size. A return to normal levels as the burn wound heals gradually restores chemical balance, temperature and pH. To date no one has produced a treatment capable of preventing the life threatening inflammatory response a burn victim can endure.
Edema In General
Edema is the term generally used to describe the accumulation of excess fluid in the intercellular (interstitial) tissue spaces or body cavities. Edema may occur as a localized phenomenon such as the swelling of a leg when the venous outflow is obstructed; or it may be systemic as in congestive heart failure or renal failure. When edema is severe and generalized, there is diffuse swelling of all tissues and organs in the body and particularly pronounced areas are given their own individual names. For example, collection of edema in the peritoneal cavity is known as “ascites”; accumulations of fluid in the pleural cavity are termed plueral effusions; and edema of the pericardial sac is termed “pericardial effusion” or “hydropericardium”. Non-inflammatory edema fluid such as accumulates in heart failure and renal disease is protein poor and referred to as a “transudate”. In contrast, inflammatory edema related to increased endothelial permeability is protein rich and is caused by the escape of plasma proteins (principally albumin) and polymorphonuclear leukocytes (hereinafter “PMNs”) to form an exudate.
Edema, whether inflammatory or non-inflammatory in nature, is thus an abnormality in the fluid balance within the microcirculation which includes the small arterioles, capillaries, and post-capillary venules of the circulatory system. Normal fluid balance and exchange is critically dependent on the presence of an intact and metabolically active endothelium. Normal endothelium is a thin, squamous epithelium adapted to permit selective, rapid exchange of water and small molecules between plasma and interstitium; but one which limits the passage of many plasma proteins.
A variety of different disturbances can induce a condition of edema. These include: an elevated venous hydrostatic pressure which may be caused by thrombosis of a vein or any other venous obstruction, heart failure; hypoproteinemia with reduced plasma oncotic pressure resulting from either inadequate synthesis or increased loss of albumin; increased osmotic pressure of the interstitial fluid due to abnormal accumulation of sodium in the body because renal excretion of sodium cannot keep pace with the intake; failure of the lymphatics to remove fluid and protein adequately from the interstitial space; an increased capillary permeabiity to fluids and proteins as occurs in the inflammatory response to tissue injury; and an increased mucopolysaccharide content within the interstitial spaces.
Currently accepted therapeutic treatments for edema include those biogenic and synthetic pharmacological agents used to treat generalized inflammations, of which edema is just one clinical manifestation. Such agents are said to inhibit the synthesis of pro-inflammatory molecules; and can include such agents as aspirin, ibuprofen (salicylates and propionate derivatives), steroids, and anti-histamines. These agents have a wide scale of effectiveness and, in general, are most valuable in the treatment of minor inflammatory problems that produce only minor, localized edemas. There are few, if any, agents that are therapeutically effective in the treatment of severe, local and systemic edemas. Furthermore, as far as is known, there is no effective agent in present use as a prophylactic against these conditions. Also, albumin infusion and congestive heart failure medications are useful in treatment of edema when used appropriately.
Current Treatments for Thermally Induced Burns
Current treatments for thermally induced burns include the use of topical agents and various surgical procedures. The topical agents that are used to treat burns are limited. Representative examples of such topical agents include, without limitation, Bacitracin, Polymyxin B Sulfate, Neomycin, Polysporin/Neosporin, Povidone, Silver Sulfadiazine, Nitrofura sp, Gentamicin, Manfenide Acetate, Nystatin, Sodium Hypochlorite Solution, Silver Nitrate, TAB Solution, and Chlorhexadine Solution. However, none of these drugs stops edema.
Due to the unacceptable rate and risk of infections from using only topical treatments (without the removal of the burned tissues), procedures called escharotomy and debridement were introduced. Escharotomy literally means cutting a hole in the eschar, the thick, rigid barrier of burn tissue. It is an emergency treatment for any full thickness, and almost invariably, circumferential burn to the dermis. It is relevant particularly to the neck, thorax and extremities. Burned skin is called eschar. Debridement is the removal of eschar tissue. Skin grafts are layers of skin, which are taken from a suitable donor area of a patient and transplanted to a recipient area of damaged skin. Using debridement alone, the rate of infection is still extremely high but with the use of skin grafts the infection rate is lowered. Pig skin and/or allografts may be used instead of the patients own skin. Debridement and skin grafts in their present form, however, do not completely restore the function of healthy skin. The transplanted skin lacks oil glands, sweat glands, hair follicles, and have no nerve endings at the injury site(s). Furthermore, the grafted skin is prone to deformities such as hypertrophic scarring. Currently it takes many months or even years to complete these extremely painful procedures.
In view of the above, there is continuing need in the art to develop better compositions and methods for treating the inflammation with edema that is associated with all forms of burns. The methods and compositions of the present invention provide for the first time a reproducible means for ameliorating and/or treating the negative effects associated with burns by blocking one or more of components of the inflammatory pathway. The inventors have satisfied these and other long felt needs with the following invention.